Table Of ContentAdvances in Experimental Medicine and Biology 1297
Jaime M. Monti
S. R. Pandi-Perumal
Eric Murillo-Rodríguez Editors
Cannabinoids
and Sleep
Molecular, Functional and Clinical Aspects
Advances in Experimental Medicine
and Biology
Volume 1297
SeriesEditors
WimE.Crusio,InstitutdeNeurosciencesCognitivesetIntégratives
d’Aquitaine,CNRSandUniversityofBordeaux,
PessacCedex,France
HaidongDong,DepartmentsofUrologyandImmunology,
MayoClinic,Rochester,MN,USA
HeinfriedH.Radeke,InstituteofPharmacology&Toxicology,Clinicofthe
GoetheUniversityFrankfurtMain,FrankfurtamMain,Hessen,Germany
NimaRezaei,ResearchCenterforImmunodeficiencies,Children'sMedical
Center,TehranUniversityofMedicalSciences,Tehran,Iran
JunjieXiao,CardiacRegenerationandAgeingLab,
InstituteofCardiovascularSciences,SchoolofLifeScience,
ShanghaiUniversity,Shanghai,China
Advances in Experimental Medicine and Biology provides a platform for
scientific contributionsinthe maindisciplines ofthe biomedicine and the life
sciences.Thisseriespublishesthematicvolumesoncontemporaryresearchin
the areas of microbiology, immunology, neurosciences, biochemistry,
biomedicalengineering,genetics,physiology,andcancerresearch.Covering
emergingtopicsandtechniquesinbasicandclinicalscience,itbringstogether
cliniciansandresearchersfromvariousfields.
Advances in Experimental Medicine and Biology has been publishing
exceptionalworksinthefieldforover40years,andisindexedinSCOPUS,
Medline (PubMed), Journal Citation Reports/Science Edition, Science
Citation Index Expanded (SciSearch, Web of Science), EMBASE, BIOSIS,
Reaxys, EMBiology, the Chemical Abstracts Service (CAS), and Pathway
Studio.
2019ImpactFactor:2.450 5YearImpactFactor:2.324
Moreinformationaboutthisseriesathttp://www.springer.com/series/5584
(cid:129) (cid:129)
Jaime M. Monti S. R. Pandi-Perumal
Eric Murillo-Rodríguez
Editors
Cannabinoids and Sleep
Molecular, Functional and Clinical
Aspects
Editors
JaimeM.Monti S.R.Pandi-Perumal
SchoolofMedicine SomnogenCanadaInc.
UniversityoftheRepublic Toronto,ON,Canada
Montevideo,Uruguay
EricMurillo-Rodríguez
DivisiónCienciasdelaSalud
UniversidadAnáhuacMayab
Merida,Mexico
ISSN0065-2598 ISSN2214-8019 (electronic)
AdvancesinExperimentalMedicineandBiology
ISBN978-3-030-61662-5 ISBN978-3-030-61663-2 (eBook)
https://doi.org/10.1007/978-3-030-61663-2
#SpringerNatureSwitzerlandAG2021
Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeor
part of the material is concerned, specifically the rights of translation, reprinting, reuse of
illustrations,recitation,broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,
andtransmissionorinformationstorageandretrieval,electronicadaptation,computersoftware,or
bysimilarordissimilarmethodologynowknownorhereafterdeveloped.
Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthis
publication does not imply, even in the absence of a specific statement, that such names are
exemptfromtherelevantprotectivelawsandregulationsandthereforefreeforgeneraluse.
Thepublisher,theauthors,andtheeditorsaresafetoassumethattheadviceandinformationin
thisbookarebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernor
the authors or the editors give a warranty, expressed or implied, with respect to the material
containedhereinorforanyerrorsoromissionsthatmayhavebeenmade.Thepublisherremains
neutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations.
ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSwitzerlandAG.
Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland
“Cannabis is the most versatile herbal remedy, and the most
useful plant on Earth. No other single plant contains as wide a
range of medically active herbal constituents.”
—Dr. Ethan Russo
Cannabinoid Research Institute
“The illegality of cannabis is outrageous, an impediment to full
utilization of a drug which helps produce the serenity and
insight, sensitivity and fellowship so desperately needed in this
increasingly mad and dangerous world.”
—Carl Sagan
This volume is dedicated to our respective families.
Foreword
For most researchers, and certainly for the general population, “cannabis”
relates totheplant and its constituents alone. However, since the mid-1980s
andearly1990s,researchhasexpandedourknowledge.Today,thecannabi-
noidfieldofsciencecoversthecannabinoidreceptors,theendocannabinoids
(particularly anandamide and 2-AG), their synthetic and degradation
pathways, and endogenous anandamide-like compounds, which are fatty
acid amides with amino acids or ethanolamines. All these entities are parts
ofamajornewphysiologicalsystem—theendocannabinoidone.Mostprob-
ably,thefieldwillexpandfurther.
Plant Cannabinoids While many dozens of plant cannabinoids are known
today,mostresearchandacquiredknowledgeareonΔ9-tetrahydrocannabinol
(THC)andcannabidiol(CBD).CBDwasisolatedinthe1930sinthelabsof
AdamsintheUSAandToddintheUK,butitsstructurewaselucidatedmany
years later—in 1963; THC was isolated in pure form, and its structure was
elucidatedonlyin1964.Thesechemicaladvancesweremademanydecades
aftertheisolationofmorphineandcocaine—thetwoothermajorillicitplant
constituents. The reason for this discrepancy seems to be the technical diffi-
cultyinisolating theplantcannabinoidsinpureform,duetothestupendous
mixtureofthisfamilyofcompoundsproducedbytheplant.Modernmethods
forseparationandpurificationnotavailablepreviouslywereneeded.
In addition to THC and CBD, there are indications that cannabigerol
(CBG)andpossiblycannabichromene(CBC)arelikewiseofmedicinalinter-
est.Verylittleisknownabouttherestoftheplantcannabinoids,exceptonthe
cannabinoid acids, which are the precursors of the neutral cannabinoids.
These acids are not stable, which seems to be the main reason why their
biologicalpropertieswerenotwellinvestigated.However,recentlyCBDacid
wasstabilized(byesterificationtoitsmethylester).ItseemstoparallelCBD
initsactions.Wealreadyknowthatitisapotentanti-nociceptive,antiemetic,
andanxiolyticcompound.Shallweseeitinthemarket,likeCBD,inallkinds
ofindustrial-preparedfoodsandbeautylotions?Ihopenot.
Most“medicalcannabis”soldtodayisintheformofmixturesinwhichthe
amountofspecificcannabinoidsvaries.Canweguesswhereweshallbewith
such mixtures or pure cannabinoids in about a decade from now? Given the
hugemarkettoday,themixtures,aswellaspureCBD,willprobablybestill
around. However, we can expect to have better-defined mixtures, as well as
ix
x Foreword
semi-syntheticCBDandCBGderivatives,asdrugsinmanyareas.Numerous
pharmaceuticalcompanieshavecannabinoidprograms.Inadditiontothepain
and anxiety mentioned above, we shall probably see synthetic and semi-
synthetic cannabinoids in additional areas of psychiatry and neurology as
wellas,presumably,ingastroenterologyandimmunology.
EndogenousCannabinoids Thediscoveryofareceptorinthe1980sledto
the isolation of endogenous cannabinoids (endocannabinoids) in the 1990s.
Two of these, anandamide and 2-AG, have been the topic of thousands of
publications. We have learned much about their chemistry, including the
synthesis and degradation of these molecules in the animal body, as well as
theirbioactivities.Theendocannabinoidsystemhasturnedouttobeacentral
one in animal physiology. Indeed in a recent review, it was stated that
“...modulating endocannabinoid activity may have therapeutic potential in
almostalldiseasesaffectinghumans.”Eventhedopaminergicorcholinergic
systemshavenotbeensodescribed.
Whataretheresearchpathwaysaheadofusinthisarea?
A. Will the endocannabinoids be investigated in
humans? More than 25 years after their discovery human studies are
almostunavailable!
B. Shallweseeadditionalendocannabinoids,which
have not been isolated so far? They may differ in their activity from
anandamideand2-AG.
C. Hastheactivityofendocannabinoidsbeenlooked
intoinallanimalbiochemicalsystems?
D. Do we know enough about the role of the
endocannabinoidsinouremotionsandpersonality?
E. Canweexpecttoseeendocannabinoidderivatives
asdrugs?
Anandamide-likeEndogenousMolecules Thebiosynthesisofanandamide
is based on fatty acid (arachidonic acid) and amino acid derivatives (an
ethanolamine). The animal body has numerous fatty acids and amino acids,
andindeed,itusestheestablishedbiosyntheticpathwayofanandamideforthe
synthesisofmanyadditional,chemicallyrelatedmolecules,mostofwhichdo
not bind to the cannabinoid receptors. Over the last two decades, several
groups have investigated these anandamide-like endogenous molecules. A
fewexamplesofsuchcompounds(testedonlyinmiceandratssofar)areas
follows:
Arachidonoylserineisneuroprotectiveafterbraintrauma.Itcausesvasodila-
tion,thusallowingbetterbloodflowintodamagedareas.
Oleoyl serine acts on osteoblasts and prevents bone loss in osteoporosis by
increasingboneformationandrestrainingboneresorption.
Oleoyl glycine has powerful anti-nicotine addiction properties. It blocks the
establishment of nicotine place preference—a test for addiction forma-
tion—and reduces withdrawal responses in nicotine-dependent mice. In
morphine-dependentrats,itwasalsofoundtoreducewithdrawalresponses
butdidnotaffectmorphineaddiction,thusdemonstratingselectivity.
Foreword xi
These are just a few examples. Many other anandamide-like compounds
are present in the animal body and act in numerous biological processes.
Indeed,ithasbeenspeculatedthatthehugenumberofsuchcompounds—the
concentration levels of which may differ from person to person—may be
involvedinthepersonalitydifferences.
Iwouldliketoendwithalookatthefutureofcannabinoiddrugs—asseen
from afar. At present, most patients who use cannabinoid-based drugs are
prescribed“medicalmarijuana”—atermthatfromamedicalpointofviewis
unacceptable. “Medical marijuana” reaching the public has to be better
defined as regards constituents, whose levels in many cases are not even
mentioned. The level of constituents in cannabis depends to a large degree
notonlyonthegeneticsoftheplantbutalsoontheconditionsunderwhichit
wasgrown.Hence,todaytheconsumptionof“medicalmarijuana”istoalarge
extent a medical gamble. As mentioned above, I believe that in most
countries, within the next few years, strict regulations will be enacted, so
that patients will always be able to get the same material as regards
constituents.
Asecondpoint—manyofthedrugsweusetodayarederivativesofnatural
products.Thus,wehavenotprescribedcortisone(animportanthormone)but
derivativesofcortisone.Suchderivativesarebettersuitedtobeusedasdrugs
than natural constituents are. It seems reasonable to expect that within a
decade pharmaceutical companies will develop derivatives of CBD and
THC, and possibly CBG, which will be used as novel drugs. We may also
have synthetic drugs, unrelated to the plant cannabinoids, which bind to the
cannabinoidreceptor,particularlytotheCB2receptor,whoseactivationdoes
notleadtomarijuana-likeactivity.
In summary, I assume that within a decade we shall have both new
cannabinoiddrugsandwell-definedextracts,usedinparallel.Letushopeso.
HebrewUniversity,MedicalFaculty, RaphaelMechoulam,PhD
PharmacySchool,
InstituteforDrugResearch,Jerusalem,Israel
